Acute toxicity of cefpirome sulfate (CPR) was examined in 6-week-old mice and rats and immature (5-day-old)rats. The LD50 values of CPR (mg/kg) were as follows : (1) mice : intravenous, 2420 (95% confidence limits, 2122-2758) for males and 2400 (2181-2640) for females ; intraperitoneal, 3850 (3407-4351) for males and 4200 (3889-4536) for females ; and oral, 16200 (14781-17755) for males and 18500 (17290-19795) for females. (2) 6-week-old rats : intravenous, 1900(1784-2023) for males and 2080(1953-2215) for females ; intraperitoneal, 6550 (6179-6943) for males and 5800(5311-6334) for females ; subcutaneous, more than 10000 for both sexes ; and oral, more than 8000 for both sexes. (3) 5-day-old rats : subcutaneous, between 1750 and 2500 for males and 2080 (1651-2621) for females. Major changes in general health conditions observed in 6-week-old mice and rats were decreased spontaneous activity, lying prone, tremor, respiratory chantes (slow or deep respiration, gasping), clonic or clonic-tonic convulsions. In the 6-week-old rats dosed subcutaneously, vocalization, writhing and cutaneous changes at the injection site (dark reddening or blackening, swelling, exfolination, depilation, induration) were also observed. In the 5-day-old rats dosed subcutaneously, the changes noted were slow respiration, writhing, cyanosis, and dark reddening and swelling of the skin at the injection site. After administration, transient depression of body weight gain or loss of body weight was observed in the mice and rats except the rats dosed orally. These changes disappeared at 7 days after administration at latest, and all surviving animals showed favorable body weight gain thereafter. Necropsied revealed hemorrhage under meninges in the brain in many of the mice and rats which died. Other findings included subcutaneous changes at the injection site in the 6-week-old and 5-day-old rats dosed subcutaneously (dark reddening, retention of dark red fluid, retention of red, white or dark red gelationous material) and changes in the peritoneal cavity in the 6-week-old rats dosed intraperitoneally (red or dark red spots on the serous membrane, reddening of dipose tissues).
A six-month intraperitoneal chronic toxicity study of cefpirome sulfate (CPR) in rats as well as a two-month recovery study were carried out at dose levels of 51.2, 128, 320 and 800 mg/kg/day. The results are as follows. 1. CPR caused no remarkable clinical signs in the general condition of the animals. 2. Body weight gain was depressed in males and females given 800 mg/kg/day. Food consumption, however, was not afected at any dose level. Water consumption incresed in males and females at dose of≥320 mg/kg/day. 3. Except an increase in urine volume in males at 800 mg/kg/day, no abnormalities in urinary parameters were found. 4. Frequent decreases in erythrocyte count, hematocrit and hemoglobin concentration were seen in males and females of the 800 mg/kg/day group. At this dose, certain males and females also showed an increase in the reticulocyte count. 5. The serum-biochemical examinations showed a very slight or slight decrease in total cholesterol in males and females given 320 mg/kg/day or more, and increases in uric acid and inorganic phosphorus concentration in some males and females given 800 mg/kg/day. 6. Very slight or slight increases in spleen weight in males and females at a dose of≥320 mg/kg/day, in thyroid weight in females at a dose of≥320 mg/kg/day and in kidney weight in males given 320 mg/kg/day or more as well as in females at 800 mg/kg/day were measured. Further, a decrease in thymus weight was seen in females of the 800 mg/kg/day group. 7. At autopsy, very slight or slight reddish browning of the thyroid was seen in males given 320 mg/kg/day or more and in females given 800 mg/kg/day. Histopathologically, the following were observed to a very slight or slight degree in the thyroid, the kidneys, the liver, the spleen and the bone marrow: in the thyroid, hypertrophy of the follicular epithelial cells in males at≥128 mg/kg/day as well as in females at≥320 mg/kg/day and deposition of yellowish brown pigment in follicular epithelial cells as well as an increase in intrafollicular coloid in males and females given 320 mg/kg/day or more; in the epithelial cells of renal tubules, hyaline droplets in males at ≥320 mg/kg/day and deposition of yellowish brown pigment in males and females given 800 mg/kg/day and, electron-microscopically, an increase in lysosomes in males and females given 800 mg/kg/day; increased extramedullary hematopoiesis in liver and spleen and an increase in erythroblastic cells in the bone marrow in some males and females at 800 mg/kg/day. 8. After the recovery period, the above-mentioned changes were attenuated or had disappeared. 9. From the data available at present, the no observable effect level of CPR is set at 51.2 mg/kg/day.
A fertility study was performed in rats by intraperitoneal administration of cefpirome sulfate (CPR) at dose levels of 0 (contro1), 200, 400 and 800 mg/kg/day. Male rats were treated for 60 days before mating and during the mating period. Female rats were administrated the substance from 14 days before mating to day 7 of pregnancy. The females were sacrificed on day 21 of pregnancy for examination of their fetuses. No animal died during the administration period. Loose feces were observed in both male and female animals in the 400 and 800 mg/kg/day groups. Body weight gain was suppressed in both male and female animals in the 800 mg/kg/day group and in male animals in the 400 mg/kg/day group. There were no significant differences in food and water intakes between treated and control groups. Autopsy revealed the enlargement of the caecum in males in the 200, 400 and 800 mg/kg/day groups. The kidney and adrenal weights were significantly increased in males in the 200, 400 and 800 mg/kg/day groups. Fertility and reproductive ability in both sexes, and estrus cycles in female rats were not affected by administration of CPR. There were no lethal effect and growth-inhibiting or teratogenic effects on the embryos and the fetuses. The results suggest that the non-effective dose level of CPR was lower than 200 and 200 mg/kg/day for general toxicity in male and female parent animals respectively, 800 mg/kg/day for reproductive ability in parent animals and in embryos and fetuses.
A teratogenicity study was pertormed in rats by intraperitoneal or intravenous administration of cefpirome sulfate (CPR) at dose level of 0 (control), 200, 400 and 800 mg/kg/day to dams from day 7 to day 17 of pregnancy. Twenty one to twenty eight female rats in each intraperitoneal and intravenous administrated group were sacrificed on day 21 of pregnancy for examination of their fetuses, and ten to thirteen female rats in each intraperitoneal administrated group were allowed to deliver for the postnatal examination of their offsprings. In the 800 mg/kg/day intravenous administrated group, two dams out of twenty four died during administration period, however no animal died in any intraperitoneal administrated group. The doses of 400 and 800 mg/kg/day caused piloerection, diarrhea or loose feces in the both administration routes, and accelerated breathing, a decrease in spontaneous activity, systemic spasms, cataleptic symptoms and wild running in the intravenous route. The suppression of body weight gain was detected in the 800 mg/kg/day intraperitoneal administrated group and 200, 400 and 800 mg/kg/day intravenous administrated groups, however there were no significant differences in food and water intakes between treated and control groups. At autopsy, enlargement of caecum and an increase in adrenal weight were detected in the 800 mg/kg/day groups of both administration routes. Body weight of the fetuses was decreased in both sexes in the 800 mg/kg/day group and in male fetuses in the 400 mg/kg/day group, and placental weight was decreased in the 800 mg/kg/day group, in the both administration routes respectively. However, embryonal or fetal mortality and incidences of external or visceral anomalies were not increased. In offspring, the dose of 800 mg/kg/day caused very slight suppression of body weight gain, however CPR had no adverse effects on the postnatal development such as viability, differentiation, emotionality, learning ability or reproductive performance. The results suggest that the non-effective dose level of CPR is 200 mg/kg/day in maternal animals and fetuses, 400 mg/kg/day in offsprings in intraperitoneal route, lower than 200 mg/kg/day in maternal animals and 200 mg/kg/day in fetuses in intravenous route respectively.
A perinatal and postnatal study was performed in rats by intraperitoneal administration of cefpirome sulfate (CPR) at dose levels of 0(control), 200, 400 and 800 mg/kg/day to dams from day 17 of pregnancy to day 21 after delivery. Twenty one or twenty two dams in each group were allowed to deliver for the postnatal examination of their offsprings. No animal died. Loose feces were observed in the 800 mg/kg/day group. Body weight gain of the dams was retarded in the 800 mg/kg/day group in the early stage of treatment. Food intake was reduced simultaneously in the 200, 400 and 800 mg/kg/day groups. Autopsy revealed the enlargement of caecum in the 800 mg/kg/day. The adrenal weight was increased in the 400 and 800 mg/kg/day groups, and the kidney weight was increased in the 800 mg/kg/day group. The body weight of pups at birth in the 80 mg/kg/day group was slightly lower than that in the control group. The body weight of male pups in the 800 mg/kg/day group decreased transiently during rearing period. However, CPR had no adverse effects on the postnatal development such as viability, differentiation, emotionality, learning ability or reproductive performance. The results suggest that the non-effective dose level of CPR is lower than 200 mg/kg/day for general toxicity, 800 mg/kg/day for reproductive ability in maternal animals and 400 mg/kg/day in offsprings respectively.
Cefpirome sulfate (CPR) was administered subcutaneously at 200, 500, and 1000 mg/kg/day to male rats for 5 weeks from 6 through 40 days of age and examinations were made to determine whether the antibiotic caused any detrimental effects on male sexual development when administered to juvenile rats. Cefotetan (CTT) was given at 1000 mg/kg/day as a positive control. Incrustation occurred at the injection site during administration in all treated groups. The CPR groups had no compoundrelated changes in fertility, spermatozoa, and reproductive organs, while the CTT group showed decreased testicular weight, abnormal fertility and spermatozoa, and atrophied germinal epithelium of seminiferous tubules, atrophied epididymis, and decreased number of spermatozoa. From the results of this investigation, it may be concluded that CPR had no effects on male sexual development when administered to juvenile rats.
Immunological properties of cefpirome sulfate (CPR) were examined. The immunogenicity and challenging ability of CPR were examined in guinea pigs by active systemic anaphylaxis (ASA) and homologous 4-hr passive cutaneous anaphylaxis (PCA) tests. The animals given CPR alone intraperitoneally for sensitization and their sera were negative for ASA or PCA reactions, like the results with reference substances, ceftazidime (CAZ) and bephalothin sodium (CET). When each antibiotic plus Freund's complete adjuvant (FCA) was used for sensitization, ASA reactions were observed with CPR, cephaloridine (CER), CET, and cefazolin sodium (CEZ), and PCA reactions, with CPR and CET. CPR had the ability to challenge the ASA and PCA reactions. CER and CET also showed the ability to challenge ASA or PCA reactions, though at low incidences. The cross-reactivity of CPR with commercially available antibiotics was examined by heterologous PCA test and by passive hemagglutination test and its inhibition test. The antiserum used was from rabbits immunized with each antibiotic-ovalbumin conjugate plus FCA, and the antigen was each antibioticbovine serum albumin conjugate. CPR cross-reacted markedly with cefotaxime sodium (CTX) having the same side chain at position 7 and showed weak, unidirectional reactions with CAZ and CET. In the in vitro direct Coombs test, the positive reactions noted with CPR were stronger than those with latamoxef sodium, equal to those with CEZ and slighter than those with CTX, CET and benzylpenicillin potassium. In conclusion, in the safety evaluation of CPR, its antigenic potential may not be a problem, like the cases of other antibiotics.
As a series of safety studies of cefpirome sulfate (CPR), its local irritancy was examined in rabbits after the following treatments : intracutaneous injection (single), application into the conjunctival sac of the eye (single), intramuscular injection (single, 7-day repeated), and intravenous injection (8-day repeated). In addition, the hemolysis test was carried out with human blood. When CPR was injected intracutaneously at a high concentration of 20%, its irritating effects were only equal to or slightly stronger than those of distilled water for injection and Na2SO4 solution. The same concentration of the compound applied into the conjunctival sac had little irritancy to the eye. In the single intramuscular administration experiment, muscular changes caused by 10% CPR were comparable to those by 0.75% acetic acid, slightly severer than those by physiological saline, and slighter than those by 6% acetic acid at 2 days after administration, but at 7 days, the changes were apparently slighter than those by 0.75% acetic acid. CPR is classified under Grade 3 according to the draft guidelines for local tolerability studies issued by the Ministry of Health and Welfare of Japan. The repeated intramuscular administration experiment showed the following results. Muscular changes caused by 10% CPR were comparable to those by physiological saline and slighter than those by 0.75% acetic acid, 5% cefotetan (CTT) and 20% cephalothin sodium (CET) at 2 days after the last administration. At 7 days, the changes were slightly severer than those by physiological saline, but slighter than those by the other control solutions. Microscopically, a tendency toward recovery was marked. In the vascular irritancy experiment, the 10% CPR group showed thrombus macroscopically on and after day 5 of dosing. Microscopy at the end of the 8-day administration period revealed thrombus and organized thrombus. In the 20% CET group, thrombogenesis was slighter than that in the 10% CPR group, while perivascular changes were severer. The changes caused by 5% CTT (thrombogenesis, perivascular changes) were somewhat severer than those by 10% CPR. In the hemolysis test, 10% CPR solution applied to fresh blood from adult men caused to hemolysis when determined by the macroscopic or spectrophotometric method.
Nephrotoxic potential of cefpirome sulfate(CPR) was examined by single and multiple intravenous administrations to Japanese white male rabbits. In single administration studies, no nephrotoxic symptoms were observed at the dose level of 320 mg/kg of CPR or less. At the dose level of 500 mg/kg or more, nephrotoxic findings were noted in both CPR and cefazolin sodium(CEZ) groups, such as proteinuria, glucosuria, increase in serum level of urea nitrogen, creatinine and uric acid, and necrosis and calcification in the proximal tubular epithelium of kidney. Renal phenolsulfonphthalein(PSP) excretion was suppressed at the dose level of 500 mg/kg of CRR or more, and 2000 kmg/kg of CEZ. In 14 and 21 days repeated administration studies, no nephrotoxic symptoms were observed at the dose level of 100 mg/kg of CPR and CEZ or less. At the dose level of 200 mg/kg of CPR or more, urinary and serum biochemical findings mentioned above were observed, and histopathological changes in the kidney described above were added in 400 mg/kg group. The similar nephrotoxic symptoms including histopathological changes of the kidney were observed in the groups of 100 mg/kg of cefaloridine(CER) and 200 mg/kg of CEZ. In addition, renal PSP excretion was suppressed in the group of 200 mg/kg of CEZ. The results would suggest that CPR is less nephrotoxic than CER and that the nephrotoxic potential of CPR is comparable to CEZ because CPR caused more severe renal failures in single administration study and less severe renal failures in multiple administration study than CEZ.